Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Damage to the cardiac myocyte sarcolemma following any of several pathological insults such as ischemia (anoxia) alone or followed by reperfusion (reoxygenation), is most apparent as progressive sarcolemmal blebbing, an event attributed by many investigators to a disruption in the underlying cytoskeletal scaffolding. Scanning electron microscopic observation of tissue cultured rat neonatal cardiomyocytes indicates that exposure of these cells to the toxic aldehyde 4-hydroxynonenal (4-HNE), a free radical-induced, lipid peroxidation product, results in the appearance of sarcolemmal blebs, whose ultimate rupture leads to cell death. Indirect immunofluorescent localization of a number of cytoskeletal components following exposure to 4-HNE reveals damage to several, but not all, key cytoskeletal elements, most notably microtubules, vinculin-containing costameres, and intermediate filaments. The exact mechanism underlying the selective disruption of these proteins cannot be ascertained at this time. Colocalization of actin indicated that whereas elements of the cytoskeleton were disrupted by increasing length of exposure to 4-HNE, neither the striated appearance of the myofibrils nor the lateral register of neighboring myofibrils was altered. Monitoring systolic and diastolic levels of intracellular calcium ([Ca2+]i) indicated that increases in [Ca2+]i occurred after considerable cytoskeletal changes had already taken place, suggesting that damage to the cytoskeleton, at least in early phases of exposure to 4-HNE, does not involve Ca(2+)-dependent proteases. However, 4-HNE-induced cytoskeletal alterations coincide with the appearance of, and therefore suggest linkage to, sarcolemmal blebs in cardiac myocytes. Although free radicals produced by reperfusion or reoxygenation of ischemic tissue have been implicated in cellular damage, these studies represent the first evidence linking cardiomyocyte sarcolemmal damage to cytoskeletal disruption produced by a free radical product.
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PMID:Cytoskeletal alterations in cultured cardiomyocytes following exposure to the lipid peroxidation product, 4-hydroxynonenal. 808 71

Heparin has potential use as an antiinflammatory treatment in many lung diseases but its therapeutic use is limited by inherent anticoagulant activity. The anticoagulant nature of heparin can be eliminated by a number of chemical treatments, but often not without loss of other important pharmacological activities. Lyophilization of porcine mucosal heparin under extreme alkaline conditions (pH > or = 13) produces a nonanticoagulant heparin remarkable for the selective loss of only 2-O and 3-O sulfates, leaving 6-O and N-sulfates intact. In contrast to the commonly used nonanticoagulant analog N-desulfated, N-reacetylated heparin, selectively O-desulfated heparin retains potent activity as an inhibitor of the cationic neutrophil proteases human leukocyte elastase and cathepsin G, both in vitro and in vivo. Selectively O-desulfated heparin also inhibits complement lysis of erythrocytes, prevents ischemia-reperfusion injury of the lung, remains a potent antiproliferative treatment for cultured airway smooth muscle and normalizes altered neuronal M2 muscarinic receptor sensitivity and bronchial hyperreactivity after antigen challenge. These retained pharmacologic properties suggest possible use of this new nonanticoagulant heparin for the treatment of a variety of lung disorders.
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PMID:Selective O-desulfation produces nonanticoagulant heparin that retains pharmacological activity in the lung. 922 56

Previous evidence suggests that both oxygen radicals and nitric oxide (NO) are important mediators of injury during renal ischemia-reperfusion (I-R) injury. However, the generation of reactive nitrogen species (RNS) has not been evaluated in this model at early time points. The purpose of these studies was to examine the development of oxidant stress and the formation of RNS during I-R injury. Male Sprague-Dawley rats were anesthetized and subjected to 40 min of bilateral renal ischemia followed by 0, 3, or 6 h of reperfusion. Control animals received a sham operation. Plasma urea nitrogen and creatinine levels were monitored as markers of renal injury. Glutathione (GSH) oxidation and 4-hydroxynonenal (4-HNE)-protein adducts were used as markers of oxidant stress. 3-Nitrotyrosine (3-NT) was used as a biomarker of RNS formation. Significant increases in plasma creatinine concentrations and urea nitrogen levels were found following both 3 and 6 h of reperfusion. Increases in GSH oxidation, 4-HNE-protein adduct levels, and 3-NT levels were observed following 40 min of ischemia with no reperfusion. Since these results suggested RNS generation during the 40 min of ischemia, a time course of RNS generation following 0, 5, 10, 20, and 40 min of ischemia was evaluated. Significant increases in 3-NT generation was detected as early as 10 min of ischemia and rose to values nearly 10-fold higher than Control at 40 min of ischemia. No additional increase was observed following reperfusion. The data clearly demonstrate that oxidative stress and RNS generation occur in the kidney during ischemia.
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PMID:Oxidative stress and reactive nitrogen species generation during renal ischemia. 1150 54

Oxidative stress and lipid peroxidation may contribute to the pathology of neurodegenerative disorders such as Alzheimer's disease (AD) and cerebral ischemia. 4-Hydroxynonenal (4-HNE) is a toxic by-product of lipid peroxidation, and immunoreactivity to 4-HNE has been used to examine lipid peroxidation in the pathogenesis of AD and ischemia. This study sought to determine 1) if there are cellular alterations in 4-HNE immunoreactivity in the human hippocampus after global ischemia, and 2) whether possession of an apolipoprotein E (APOE) epsilon4 allele influenced the extent of 4-HNE immunoreactivity. 4-HNE immunoreactivity was assessed semi-quantitatively in the temporal lobe of a group of controls (n = 44) and in a group of patients who had an episode of global ischemia as a result of a cardiorespiratory arrest and subsequently died (n = 56, survival ranged from 1hr to 42 days). There was minimal cellular 4-HNE immunoreactivity in the control group. However, compared to controls, 4-HNE immunoreactivity was significantly increased in neurons (p < 0.0002) and glia (p < 0.0001) in the hippocampal formation after global ischemia. Possession of an APOE epsilon4 allele did not influence the extent of neuronal or glial 4-HNE immunostaining in the control or global ischemia group. There was a significant negative correlation between the extent of neuronal 4-HNE immunoreactivity with survival period after global ischemia (r2 = 0.0801; p < 0.036) and a significant positive correlation between the extent of glial 4-HNE immunoreactivity and survival after global ischemia (r2 = 0.2958; p < 0.0001). The data indicate a marked increase in neuronal and glial 4-HNE. This substantiates a role for lipid peroxidation in the pathogenesis of cerebral ischemia. There was no indication that APOE genotype influenced the extent of 4-HNE immunoreactivity.
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PMID:4-Hydroxynonenal immunoreactivity is increased in human hippocampus after global ischemia. 1155 86

Melatonin, a pineal secretory product, synthesized from l-tryptophan, has received increased attention because of its antioxidative and immunomodulatory properties. It has been detected in the gut and shown to protect the gastric mucosa, and liver from acute damage, but the role of melatonin in the protection of the pancreas against acute inflammation is not clear. The aim of this study was to investigate the effects of melatonin and its precursor, l-tryptophan, on caerulein-induced pancreatitis (CIP) and on ischemia/reperfusion (I/R)-provoked pancreatitis in rats. CIP was induced by subcutaneous infusion of caerulein to the rats (25 microg/kg). I/R was induced by clamping of the inferior splenic artery for 30 min followed by 2 hr of reperfusion. Melatonin (10, 25 or 50 mg/hr) or l-tryptophan (50, 100 or 250 mg/kg) was given as a bolus intraperitoneal (i.p.) injection 30 min prior to the onset of pancreatitis. CIP and I/R were confirmed by histologic examination and manifested by typical pancreatic edema, by an increase of plasma levels of amylase (by 500% in CIP and by 40% in I/R) and the pro-inflammatory tumor necrosis factor alpha (TNFalpha) (by 500%). Lipid peroxidation products such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), were increased several fold in the pancreas CIP and I/R, whereas pancreatic blood flow (PBF) was significantly reduced in these animals. Pretreatment of rats subjected to CIP or to I/R with melatonin (25 or 50 mg/kg i.p.) or l-tryptophan (100 or 250 mg/kg i.p.) significantly reduced pancreatic edema, plasma levels of amylase and TNFalpha and diminished pancreatic MDA + 4-HNE contents, while enhancing PBF, pancreatic integrity and plasma levels of the anti-inflammatory interleukin 10 (IL-10). This was accompanied by a marked and dose-dependent rise of plasma melatonin immunoreactivity. Gene expression of N-acetyl transferase, an enzyme involved in melatonin biosynthesis, was detected in the pancreas of normal rats and was significantly enhanced in the rats with CIP. We conclude that exogenous melatonin, and that produced from l-tryptophan, attenuates pancreatic damage induced by CIP or by I/R and this effect may be attributable to the reduction in lipid peroxidation and TNFalpha release combined with an increase of plasma anti-inflammatory IL-10 in rats with acute pancreatitis.
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PMID:Protective effect of melatonin and its precursor L-tryptophan on acute pancreatitis induced by caerulein overstimulation or ischemia/reperfusion. 1248 71

The haemorrhagic transformation in ischemic stroke involves disruption of the integrity of the microvascular beds, partially based on the action of matrix metalloproteinases (MMPs). The objective of the present study was to evaluate the contribution of microvascular endothelial cells from human brain (HBECs) to MMPs' expression and regulation under conditions relevant to brain ischemia. MMPs and their inhibitors were examined with zymography, Western-blotting, ELISA and MMP-activity assay in cultured HBECs. Four-hour hypoxia (pO(2)=60 mmHg) elevated the level of MMP-9 in the supernatant of the HBECs and this early response required collagen-matrix. Active oxygen species sustained the increased MMP-9 activity for at least 24 h. In the post-hypoxic period 20 micro mol/L H(2)O(2) caused a 6-fold increase in the specific activity of MMP-9 over the normoxic cells and a comparable effect was exerted by thrombin (50 nmol/L) and leukocyte elastase (10 nmol/L). The role of NF-kappaB, a redox-state sensitive transcription factor, was evaluated with immunofluorescence confocal microscopy and immunoblotting of nuclear and cytoplasmic extracts. The oxidative stress-dependent MMP-9 induction was accompanied by a significant increase in the NF-kappaB localized in the nuclei and these responses were blunted with a proteasome inhibitor (MG132). Consequently, according to our in vitro data HBECs are a source of MMP-9, which is under the control of triggers relevant to the ischemic/reperfused brain (reactive oxygen species, thrombus and inflammation related proteases) and this regulation is partially based on NF-kappaB activation. The reported regulation of endothelium-derived MMP-9 supports its potential involvement in the post-hypoxic disturbances of the cerebral microcirculation.
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PMID:Matrix metalloproteinase-9 expression in post-hypoxic human brain capillary endothelial cells: H2O2 as a trigger and NF-kappaB as a signal transducer. 1295 23

Oxidative stress occurs as a result of reactive oxygen species (ROS) overproduction. The content of carbonyl groups (CG), malonyldialdehyde, 4-hydroxynonenal (MDA, 4-HNE) represent markers of protein and lipid peroxidation processes, respectively. The aim of the present study was to determine CG and MDA/4-HNE in the serum of 30 hemodialyzed patients (-HD; 13 men, 17 women of mean age 47.7 +/- 15.3 years) before and after a hemodialysis session, of 20 transplant patients (TX; 10 men, 10 women of mean age 40.7 +/- 11.3 years) before and after the procedure (RT), and of a control group (n = 47; including 30 women, 17 men of mean age 38.7 +/- 14.0 years). The CG content was evaluated using the 2,4-dinitrophenylhydrazine assay and MDA/4-HNE by the Oxis Bioxytech colorimetric method. Among the HD group the concentrations of MDA/4-HNE and CG were higher than control subjects (P <.05). In the HD group CG concentrations before and after dialysis session were similar while MDA/4-HNE concentrations were higher before the dialysis session (P <.01). One day after RT, MDA/4-HNE and CG concentrations had increased but at 7 days they had decreased and the CG level was increased. A high production of ROS can be assumed in dialysis patients. MDA/4-HNE concentrations, however, decreased after the dialysis treatment, because as low-weight molecules they diffused across the dialysis filter. On the first day after RT a high intensity of lipid and protein peroxidation was observed. During the first week after RT, accumulation of protein peroxidation products was observed but simultaneously lipid peroxidation product concentrations decreased due to quick metabolism. The intensity of lipooxidation during first day after RT seems to be dependent upon the ischemia time.
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PMID:Influence of predialysis oxidative stress on peroxidation processes after renal transplantation. 1452 78

In Germany, hydroalcoholic extracts from hawthorn (Crataegus spp.) leaves with flowers are approved drugs for the treatment of mild forms of heart insufficiency. Besides cardiotonic effects these herbal remedies have been shown to possess cardioprotective properties. We now evaluated if treatment of rats with the Crataegus special extract WS 1442 also improves cardiac function and prevents myocardial infarction during prolonged ischemia and reperfusion lasting for 240 and 15 min, respectively. Oral administration of WS 1442 (10 or 100 mg x kg(-1) x day(-1)) for 7 days before ligation of the left coronary artery dose-dependently suppressed the decrease of the pressure rate product. WS 1442 treatment also attenuated the elevation of the ST-segment in the ECG, diminished the incidence of ventricular fibrillations (control: 67%; 10 mg x kg(-1): 64%; 100 mg x kg(-1): 27%) and reduced the mortality rate (control: 47%; 10 mg.kg(-1): 27%; 100 mg x kg(-1): 9%). Furthermore, the area of myocardial infarction within the ischemic zone was significantly smaller in treated rats (10 mg x kg(-1): 64.3 +/- 5.1%; 100 mg x kg(-1): 42.8 +/- 4.1%) when compared with controls (78.4 +/- 2.6%). It is suggested that these pharmacological effects are accounted for by the combined antioxidative, leukocyte elastase inhibiting and endothelial nitric oxide (NO) synthesis enhancing properties of WS 1442.
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PMID:Crataegus special extract WS 1442 improves cardiac function and reduces infarct size in a rat model of prolonged coronary ischemia and reperfusion. 1476 75

White matter of the neonatal brain is highly sensitive to hypoxic-ischemic insult. The susceptibility of premature oligodendrocytes (OLs) to free radicals (FRs) produced during hypoxia-ischemia (HI) has been proposed as one of the mechanisms involved. To test this hypothesis, and to further investigate if the FR scavenger alpha-phenyl-N-tert-butyl-nitrone (PBN) attenuates hypoxic-ischemic white matter damage (WMD), postnatal day 4 (P4) SD rats were subjected to bilateral common carotid artery ligation (BCAL), followed by 8% oxygen exposure for 20 min. Pathological changes were evaluated on P6 and P9, 2 and 5 days after the HI insult. HI caused severe WMD including rarefaction, necrosis and cavity formation in the corpus callosum, external and internal capsule areas. OL injury was evidenced by degeneration of O4 positive OLs on P6. Disrupted myelination was verified by decreased immunostaining of myelin basic protein (MBP) on P9. Axonal injury was demonstrated by increased amyloid precursor protein (APP) immunostaining on both P6 and P9. Two lipid peroxidation end products, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), showed a one-fold elevation within 1-24 h following HI. 4-HNE immunostaining was found to specifically localize in the white matter area. Furthermore, pyknotic O4+ OLs were double-labeled with 4-HNE. These findings suggest that FRs are involved in the pathogenesis of neonatal WMD. PBN (100 mg/kg, i.p.) treatment alleviated the pathological changes of WMD following HI. It improved the survival of O4 positive OLs, attenuated hypomyelination and reduced axonal damage. PBN treatment also decreased the brain concentration of MDA/4-HNE and positive 4-HNE staining in the white matter area. These findings indicate that in the current WMD model, PBN protects both OLs and axons, the two main components in the white matter, from neonatal HI insult. FR scavenging appears to be the primary mechanism underlying its neuroprotective effect.
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PMID:alpha-Phenyl-n-tert-butyl-nitrone attenuates hypoxic-ischemic white matter injury in the neonatal rat brain. 1506 44

Free radicals induced by cerebral ischemia-reperfusion injury can trigger lipid peroxidation, leading to the production of malondialdehyde (MDA) and 4-hydroxy-2(E)-nonenal (4-HNE). Post-ischemia electroacupuncture (EA) therapy was able to reduce extent of lipid peroxidation. However, the effect of pre-ischemic EA therapy has not been reported. In this study, we aim to investigate the effectiveness of pre-ischemic EA therapy on lipid peroxidation in the rat ischemic injury model. Four groups of Sprague-Dawley rats were designed: Placebo group (without EA therapy), NA group (EA therapy on non-acupoint), GB20 group (EA therapy on Fengchi), and ST36 group (EA therapy on Zusanli). Half of each group (n = 6) received 30-minute EA therapy for 3 times and the other half group for 18 times before the occlusion of right middle cerebral artery. Right brains were taken for determination of concentration of MDA and the total of MDA plus 4-HNE. We found that multiple pre-ischemia EA therapy at either GB20 or ST36 can effectively reduce the amount of MDA produced after MCA occlusion. However, this reduction was not observed in the total amount of MDA and 4-HNE. In conclusion, pre-ischemia EA can partly regulate the lipid peroxidation in cerebral ischemia, where both GB20 and ST36 have a similar beneficial effectiveness.
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PMID:Effectiveness of multiple pre-ischemia electro-acupuncture on attenuating lipid peroxidation induced by cerebral ischemia in adult rats. 1523 90


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